Autophagic cell death induced by pH modulation for enhanced iron-based chemodynamic therapy.

Iron-based chemodynamic therapy (CDT) exhibits commendable biocompatibility and selectivity, but its efficacy is constrained by the intracellular pH of tumors. To overcome this obstacle, we constructed a silica delivery platform loaded with autophagy-inducing reagents (rapamycin, RAPA) and iron-based Fenton reagents (Fe3O4). This platform was utilized to explore a novel strategy that leverages autophagy to decrease tumor acidity, consequently boosting the effectiveness of CDT. Both in vitro and in vivo experiments revealed that RAPA prompted the generation of acidic organelles (e.g., autophagic vacuoles and autophagosomes), effectively changing the intracellular pH in the tumor microenvironment. Furthermore, RAPA-induced tumor acidification significantly amplified the efficacy of Fe3O4-based Fenton reactions, consequently increasing the effectiveness of Fe3O4-based CDT. This innovative approach, which leverages the interplay between autophagy induction and iron-based CDT, shows promise in overcoming the limitations posed by tumor pH, thus offering a more efficient approach to tumor treatments.

A Novel Frameshift Variant of the ELF4 Gene in a Patient with Autoinflammatory Disease: Clinical Features, Transcriptomic Profiling and Functional Studies.

We described the diagnosis and treatment of a patient with autoinflammatory disease, named "Deficiency in ELF4, X-linked (DEX)". A novel ELF4 variant was discovered and its pathogenic mechanism was elucidated. The data about clinical, laboratory and endoscopic features, treatment, and follow-up of a patient with DEX were analyzed. Whole exome sequencing and Sanger sequencing were performed to identify potential pathogenic variants. The mRNA and protein levels of ELF4 were analyzed by qPCR and Western blotting, respectively. The association of ELF4 frameshift variant with nonsense-mediated mRNA decay (NMD) in the pathogenesis DEX was examined. Moreover, RNA-seq was performed to identify the key molecular events triggered by ELF4 variant. The relationship between ELF4 and IFN-ß activity was validated using a dual-luciferase reporter assay and a ChIP-qPCR assay. An 11-year-old boy presented with a Behçet's-like phenotype. The laboratory abnormality was the most obvious in elevated inflammatory indicators. Endoscopy revealed multiple ileocecal ulcers. Intestinal histopathology showed inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-α blocker (adalimumab), which reaped an excellent response over 16 months of follow-up. Genetic analysis identified a maternal hemizygote frameshift variant (c.1022del, p.Q341Rfs*30) in ELF4 gene in the proband. The novel variant decreased the mRNA level of ELF4 via the NMD pathway. Mechanistically, insufficient expression of ELF4 disturbed the immune system, leading to immunological disorders and pathogen susceptibility, and disrupted ELF4-activating IFN-ß responses. This analysis detailed the clinical characteristics of a Chinese patient with DEX who harbored a novel ELF4 frameshift variant. For the first time, we used patient-derived cells and carried out transcriptomic analysis to delve into the mechanism of ELF4 variant in DEX.

A rare case of primary central nervous system histiocytic sarcoma harboring a novel ARHGAP45::BRAF fusion: a case report and literature review.

INTRODUCTION: Patients with histiocytic sarcoma occurring in the central nervous system (CNS) are rare and have a very poor prognosis. The increased use of molecular diagnostic approaches in solid tumors has brought more opportunities for the diagnosis and treatment of central nervous system histiocytic sarcoma (CNSHS). CASE DESCRIPTION: A 9-year-old girl was admitted to the hospital with pain in her head and neck, as well as vomiting. Imaging scans showed a prominent abnormality in the anterior falciform region, and histopathology revealed the presence of CD68 (+) and CD163 (+) cells, leading to a preliminary diagnosis of primary intracerebral CNSHS. Molecular profiling tests identified a new variant of ARHGAP45::BRAF fusion in this case, which has not been reported in any other tumor. The patient underwent surgical removal of the tumor and will require long-term monitoring. CONCLUSION: The presence of the BRAF point mutation, predominantly BRAF p.V600E, has been documented in prior literature of CNSHS. This is the first case of pediatric histiocytic sarcoma in the anterior falciform region who has a unique ARHGAP45::BRAF fusion. The findings of our study indicate that a broader range of molecular assays should be employed in the diagnosis of CNSHS and opens up new possibilities for the treatment of the patient.

Correlation between neutrophil gelatinase phase lipocalin and cerebral small vessel disease.

Background: Cerebral small vessel disease (CSVD) is common in the elderly population. Neutrophil gelatinase-associated lipocalin (NGAL) is closely related to cardiovascular and cerebrovascular diseases. NGAL causes pathological changes, such as damage to the vascular endothelium, by causing inflammation, which results in other related diseases. The purpose of this study was to investigate whether serum NGAL levels could predict disease severity in patients with CSVD. Methods: The patients with CSVD who visited the Department of Neurology at the First Affiliated Hospital of Zhengzhou University between January 2018 and June 2022 were prospectively included. The total CSVD burden score was calculated using whole-brain magnetic resonance imaging (MRI), and the patients were divided into a mild group (total CSVD burden score < 2 points) and a severe group (total CSVD burden score ≥ 2 points). Age, sex, height, smoking and alcohol consumption history, medical history, and serological results of patients were collected to perform the univariate analysis. Multivariate logistic regression was used to analyze the risk factors that affect CSVD severity. The multiple linear regression method was used to analyze which individual CSVD markers (periventricular white matter hyperintensities, deep white matter hyperintensities, lacune, and cerebral microbleed) play a role in the association between total CSVD burden score and NGAL. Results: A total of 427 patients with CSVD (140 in the mild group and 287 in the severe group) were included in the study. A multivariate logistic regression analysis showed that the following factors were significantly associated with CSVD severity: male sex [odds ratio(OR), 1.912; 95% confidence interval (CI), 1.150-3.179], age (OR, 1.046; 95% CI, 1.022-1.070), history of cerebrovascular disease (OR, 3.050; 95% CI, 1.764-5.274), serum NGAL level (OR, 1.005; 95% CI, 1.002-1.008), and diabetes (OR, 2.593; 95% CI, 1.424-4.722). A multivariate linear regression shows that periventricular white matter hyperintensities and cerebral microbleed are associated with serum NGAL concentrations (P < 0.05). Conclusion: Serum NGAL level is closely related to CSVD severity and is a risk factor for the burden of CSVD brain damage. Serum NGAL has high specificity in reflecting the severity of CSVD.

Tumor microenvironment-mediated NIR-I-to-NIR-II transformation of Au self-assembly for theranostics.

The misdiagnosis of tumors due to insufficient penetration depth or signal interference and damage to normal tissues due to indiscriminate treatment are the biggest challenges in using photothermal agents for clinical translation. To overcome these limitations, a strategy of switching from the near-infrared (NIR)-I region to the NIR-II region was developed based on tumor microenvironment (TME)-mediated gold (Au) self-assembly. Using zeolitic imidazolate framework-8 (ZIF-8) metal-organic framework-coated gold nanorods (AuNRs@ZIF-8) as a model photothermal agent, we demonstrated that only a NIR-I photoacoustic imaging signal was observed in normal tissue because ZIF-8 could prevent the aggregation of AuNRs. However, when ZIF-8 dissociated in the TME, the AuNRs aggregated to activate NIR-II photoacoustic imaging and attenuate the NIR-I signal, thereby allowing an accurate diagnosis of tumors based on signal transformation. Notably, TME-activated NIR-II photothermal therapy could also inhibit tumor growth. Therefore, this TME-activated NIR-I-to-NIR-II switching strategy could improve the accuracy of deep-tumor diagnoses and avoid the injury caused by undifferentiated treatment. STATEMENT OF SIGNIFICANCE: Photothermal agents used for photoacoustic imaging and photothermal therapy have garnered great attention for tumor theranostics. However, always "turned on" near-infrared (NIR)-I laser (700-1000 nm)-responsive photothermal agents face issues of penetration depth and damage to normal tissues. In contrast, tumor microenvironment-activated NIR-II "smart" photothermal agents exhibit deeper penetration depth and tumor selectivity. Therefore, a NIR-I-to-NIR-II switching strategy was developed based on tumor microenvironment-mediated Au self-assembly. This work provides a new strategy for developing tumor microenvironment-activated NIR-II smart photothermal agents.

Therapeutic Effect of Polaprezinc on Reflux Esophagitis in the Rat Model.

BACKGROUND/AIMS: To explore the protective effects and therapeutic mechanism of Esomeprazole (PPI), polaprezinc granule (PZ), and PPI + PZ on reflux esophagitis (RE) in the rat model. METHODS: Wistar rats were randomly divided into 9 groups, which contain the control group, the acid cessation group (0.7% HCl, Q3D × 4), and the acid persistence group (0.7% HCl, Q3D × 11). PPI was administered by gavage at 8 mg·kg-1 body weight and PZ was administered by gavage at 120 mg·kg-1 body weight once a day for 15 days. The gastric cardia tissue of the feeding tube was observed under the light microscope, and the levels of interleukin-8 (IL-8) and prostaglandin E2 (PGE2) were measured by ELISA. The expression of EGFR, Akt, p-Akt, and p-mTOR was detected by Western blot. RESULTS: The ELISA results showed that the levels of IL-8 and PGE2 were significantly increased in the model group, but decreased in all groups after treatment. In the acid cessation group, PZ treatment had the most significant effect on reducing IL-8 levels and PPI + PZ treatment had the most significant effect on reducing PGE2 levels. In the acid persistence group, the PPI treatment had the most significant effect on reducing the levels of IL-8 and PGE2, and the PZ treatment could also significantly reduce their levels, close to the normal value. Western blot results showed that the expression of PI3K/Akt/mTOR pathway protein was increased in the model group, while its expression was decreased after treatment. CONCLUSIONS: Polaprezinc has a significant therapeutic effect on RE in rats, which can reduce the levels of IL-8 and PGE2 and downregulate the expression of PI3K/Akt/mTOR signal pathway protein. The efficacy of polaprezinc in the treatment of reflux esophagitis is comparable to that of PPI, and the combination of them is more effective in the reflux esophagitis treatment.

Amniotic fluid stem cell attenuated necrotizing enterocolitis progression by promoting Rspo3/AMPKα axis.

R-spondin 3 (Rspo3) is involved in various cellular processes. The alteration of Rspo3 participates in the differentiation of intestinal epithelial cells which are the crucial effector cells during necrotizing enterocolitis (NEC) development. Amniotic fluid stem cells (AFSCs) were recently indicated as a potential approach for NEC therapy. This study aimed to illustrate the regulatory role and mechanism of Rspo3 in the pathogenesis of NEC and whether AFSCs therapy would impact NEC by mediating Rspo3. First, the alteration of Rspo3 was investigated in the serum and tissues of NEC patients, and an in vitro cell model induced by LPS. A gain-of-function assay was conducted to explore the function of Rspo3 in NEC. Through the analysis of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) activation, the mechanism of Rspo3-mediated NEC progression was demonstrated. Finally, AFSCs were used to coculture human intestinal epithelial cells (HIECs) and the impacts on NEC development were also explored. The results found that Rspo3 was dramatically depressed during NEC progression and reversing Rspo3 expression ameliorated LPS-induced injury, inflammation, oxidative stress and tight junction dysregulation in HIECs. Besides, Rspo3 overexpression reversed AMPKα inactivation induced by NEC and an AMPKα inhibitor, Compound C, blocked the effect of Rspo3 overexpression on NEC. AFSCs treatment was beneficial for NEC therapy by restoring Rspo3 expression which was counteracted by exosome inhibitor. Generally, AFSCs attenuated NEC progression by promoting the Rspo3/AMPKα axis which might exert via the secretion of exosomes. Our conclusions might be valuable for NEC diagnosis and therapy.

Tumor microenvironment responsive T1-T2 dual-mode contrast agent Fe3O4@ZIF-8-Zn-Mn NPs for in vivo magnetic resonance imaging.

Activated T1-T2 contrast agents can effectively improve the sensitivity and diagnosis accuracy of magnetic resonance imaging (MRI), but the construction of such contrast agents still remains a great challenge. In this work, a pH- and glutathione (GSH)-responsive T1-T2 dual-mode contrast agent, Fe3O4@ZIF-8-Zn-Mn nanoparticles (NPs), with simple components was constructed via simply assembly of paramagnetic Mn2+ ions (as T1 contrast agent) and Fe3O4 NPs (as T2 contrast agent) into a pH- and GSH-sensitive Zn-zeolitic imidazole framework (ZIF-8) matrix. Under neutral conditions, Fe3O4@ZIF-8-Zn-Mn NPs show good stability and weak T1-T2 dual-mode MRI contrast effect (r1 = 0.82 mM-1 s-1, r2 = 21.28 mM-1 s-1) due to the magnetic interference between Fe3O4 NPs and paramagnetic Mn2+ ions. In contrast, under acidic environment (pH = 6.5-5.5) and in the present GSH (0-4 mM), Fe3O4@ZIF-8-Zn-Mn NPs can be disassembled and release Fe3O4 NPs and paramagnetic Mn2+ ions, which causes simultaneous recovery of T1 and T2 imaging performances with enhanced r1 and r2 relaxation values up to 6.9 and 9.9 times, respectively. Moreover, in vivo MRI experiments showed that after the intravenous injection of Fe3O4@ZIF-8-Zn-Mn NPs for about one hour, the T1-weighted imaging of the tumor site becomes brighter with T1 signal enhanced by about 31%, while the T2-weighted imaging of the tumor site becomes darker with T2 signal enhanced by nearly 30%, suggesting the great potential of Fe3O4@ZIF-8-Zn-Mn NPs to be used as a tumor microenvironment-responsive T1-T2 dual-mode contrast agent for sensitive tumor imaging.

Novel Classification System of Adenoids Based on Appearance and Its Relationship with Drug Therapy.

INTRODUCTION: Adenoidectomy is a common procedure in children who have adenoid hypertrophy (AH), but anesthesia risks should be considered. We proposed a novel classification system for adenoids based on their appearance. Additionally, we explored whether the novel classification of adenoids correlates with the response to therapy and thus might be helpful for further treatment recommendations. METHODS: We used fiberoptic nasal endoscopy to determine the degree and appearance of AH. Obstructive Sleep Apnea Questionnaire (OSA-18) was used to assess the quality of life of children with AH. The adenoids were divided into three types: edematous type, common type, and fibrous type. In adenoid tissues, the eosinophils were counted. Immunohistochemistry and Western blot were done to determine the expression of CysLTR1, CysLTR2, CGR-α, and CGR-ß in different types of adenoids. RESULTS: 70.67% (106/150) of AH patients presented with allergic rhinitis (AR), and of them, 68% (72/106) of adenoids were the edematous type. The expressions of CGR-α, CGR-ß, and eosinophil count were higher in the edematous compared with the common and fibrous types. The expression of the leukotriene receptor was similar in all types. Upon montelukast combined with nasal glucocorticoid therapy, improvement of OSA-18 scores and AH grade was significantly compared to montelukast monotherapy for edematous type. There was not any statistically significant difference between the scores upon montelukast combined with nasal glucocorticoid and montelukast monotherapy for common and fibrous type. We observed a positive correlation between eosinophil count in the blood and in the adenoid tissue. CONCLUSION: AR was the risk factor for the development of edematous AH. All subtypes of AH responded to montelukast, while there was an additional effect of nasal glucocorticoid in the edematous type. A combination therapy of nasal glucocorticoid with leukotriene receptor antagonist can be recommended for AH patients with AR, patients with edematous adenoids, and/or patients with increased eosinophils in blood routine.

Significance of laparoscopic cytoreductive surgery for appendiceal pseudomyxoma peritonei with limited disease and low tumor burden.

OBJECTIVE: To investigate the clinical value of laparoscopic cytoreductive surgery (CRS) in treating of appendiceal pseudomyxoma peritonei with limited disease and low tumor burden. METHODS: The clinical data of patients with appendiceal pseudomyxoma peritonei treated by surgery with CRS at the Aerospace Center Hospital from January 2018 to December 2021 were retrospectively analyzed. The patients were divided into laparoscopic or open CRS groups according to the operation method. A propensity score-matched (PSM) analysis (1:1) was performed, the related clinical variables were compared between the two groups, and the effect on progression-free survival (PFS) was also analyzed. RESULTS: One hundred and eight patients were included in this study. After PSM, 33 patients were selected from each group and the age and peritoneal cancer index were matched between the two groups. There were significant differences in operation time (P < 0.001), intraoperative bleeding (P < 0.001), intraoperative blood transfusion (P = 0.007), hospital stay (P < 0.001). The analysis of PFS showed that there was no significant difference between the two operation methods. After multivariate analysis, the pathologic subtype (P = 0.012) was identified as an independent prognostic factor for PFS. CONCLUSION: The curative effect of laparoscopic CRS is like that of open operation, which can significantly shorten the operation time and hospital stay and reduce intraoperative bleeding and blood transfusion event. The laparoscopic CRS is safe and feasible in strictly selected patients. The pathologic subtype is an independent factor affecting the prognosis for PFS.

Exploring the alterations and function of skin microbiome mediated by ionizing radiation injury.

Background: Radiation-induced skin injury (RISI) is still the most common and severe side effect of radiotherapy. The role of the skin's microbial barrier in the pathogenesis and progression of RISI needs to be fully investigated. Methods: This study aimed to explore the alterations in and functions of the skin microbiota in RISI. We applied the unculturable approach to characterize the cutaneous microbiomes of a radiation-induced animal model by sequencing the V1-V3 regions of the 16S ribosomal RNA (rRNA) gene. Combined with the downloaded clinical data of patients, a comprehensive analysis was performed to identify potential radioprotective species and metabolic pathways. Results: There were no significant differences in the alpha diversity indices (Sobs, Shannon, Simpson, Ace, and Chao) between the acute radiation injury and control groups. Phylum-level analysis of the RISI microbiomes exhibited significant predominance of Firmicutes (mean abundance = 67%, corrected p = 0.0035). The high abundance of Firmicutes was significantly associated with rapid healing of RISI (average relative abundance = 52%; Kruskal-Wallis: p = 5.7E-4). Among its members, Streptococcus, Staphylococcus, Acetivibrio ethanolgignens group, Peptostreptococcus, Anaerofilum, and UCG-002 [linear discriminant analysis (LDA) > 3, p < 0.05] were identified as the core genera of Firmicutes. In addition, Lachnosiraceae and Lactobacillus occupied an important position in the interaction network (r > 0.6, p < 0.05). The differential metabolic pathways of RISI were mainly associated with carbohydrate metabolism (butanoate and propanoate metabolism), amino acid metabolism (tryptophan and histidine metabolism), energy metabolism, and lipid metabolism (fatty acid degradation and biosynthesis). Conclusion: This study provides new insights into the potential mechanism and skin microbial changes in the progression of RISI. The overwhelming predominance of members of Firmicutes, including Streptococcaceae, Staphylococcaceae, Lachnospiraceae, and Lactobacillus, is potentially related to rapid healing of RISI. The microbiota-metabolite axis plays a critical role in RISI and provides promising therapeutic targets for the treatment of adverse side effects.

Engineering of an endogenous hydrogen sulfide responsive smart agent for photoacoustic imaging-guided combination of photothermal therapy and chemotherapy for colon cancer.

INTRODUCTION: Photothermal therapy can be synergistically combined with chemotherapy to improve the therapeutic effect for colon cancer. However, conventional therapeutic agents have side effects in normal tissues, limiting their application. OBJECTIVES: To reduce these side effects, a smart agent (Cur@HKUST-1@PVP) whose functionality is triggered by the high content of endogenous hydrogen sulfide in colon tumors was engineered for photoacoustic imaging-guided combination of photothermal therapy and chemotherapy for colon tumors. METHODS: After reacting with hydrogen sulfide, Cur@HKUST-1@PVP simultaneously generates CuS and releases curcumin. The generated CuS serves as an imaging agent for both photothermal therapy and photoacoustic imaging, while the released curcumin is used for chemotherapy. RESULTS: In vivo photoacoustic imaging experiments demonstrated that Cur@HKUST-1@PVP can be used for selectively imaging colon cancer tumors. In vivo experiments in mice for treatment suggested that the endogenous hydrogen sulfide-activated combination of photothermal therapy and chemotherapy has a better treatment effect that photothermal therapy or chemotherapy treatment alone. CONCLUSION: The endogenous hydrogen sulfide-activated Cur@HKUST-1@PVP agent developed herein shows great potential for the accurate diagnosis and effective treatment of colon cancer.

Exploring Potential Biomarkers, Ferroptosis Mechanisms, and Therapeutic Targets Associated with Cutaneous Squamous Cell Carcinoma via Integrated Transcriptomic Analysis.

Background: Cutaneous squamous cell carcinoma (cSCC) is the leading cause of death in patients with nonmelanoma skin cancers (NMSC). However, the unclear pathogenesis of cSCC limits the application of molecular targeted therapy. Methods: Three microarray datasets (GSE2503, GSE45164, and GSE66359) were downloaded from the Gene Expression Omnibus (GEO). After identifying the differentially expressed genes (DEGs) in tumor and nontumor tissues, five kinds of analyses, namely, functional annotation, protein-protein interaction (PPI) network, hub gene selection, TF-miRNA-mRNA regulatory network analysis, and ferroptosis mechanism, were performed. Results: A total of 146 DEGs were identified with significant differences, including 113 upregulated genes and 33 downregulated genes. The enriched functions and pathways of the DEGs included microtubule-based movement, ATP binding, cell cycle, P53 signaling pathway, oocyte meiosis, and PLK1 signaling events. Nine hub genes were identified (CDK1, AURKA, RRM2, CENPE, CCNB1, KIAA0101, ZWINT, TOP2A, and ASPM). Finally, RRM2, AURKA, and SAT1 were identified as significant ferroptosis-related genes in cSCC. The differential expression of these genes has been verified in two other independent datasets. Conclusions: By integrated bioinformatic analysis, the hub genes identified in this study elucidated the molecular mechanism of the pathogenesis and progression of cSCC and are expected to become future biomarkers or therapeutic targets.

Ellagic Acid Increases Stress Resistance via Insulin/IGF-1 Signaling Pathway in Caenorhabditis elegans.

Ellagic acid is a natural polyphenol found in various fruits and vegetables. Numerous studies have shown that ellagic acid has beneficial effects on human health. In this study, we investigated the stress resistant action of ellagic acid in Caenorhabditis elegans (C. elegans). Notably, 50 µM ellagic acid prolonged the lifespan of C. elegans by 36.25%, 36.22%, 155.1%, and 79.07% under ultraviolet radiation stress, heat stress, oxidative stress, and Pseudomonas aeruginosa infection stress, respectively. Furthermore, the mechanism by which ellagic acid reduces the damage caused by ultraviolet radiation in C. elegans was explored. Ellagic acid could significantly induce the nucleus translocation of DAF-16 and, thereby, activate a series of target genes to resist ultraviolet radiation stress. Moreover, ellagic acid also significantly increased the expression of SOD-3 by 3.61 times and the activity of superoxide dismutase by 3.70 times to clean out harmful reactive oxygen species in C. elegans exposed to ultraviolet radiation stress. In both daf-16 mutant and daf-2; daf-16 double-mutant worms exposed to ultraviolet radiation, ellagic acid could no longer prolong their lifespan. These results indicate that ellagic acid plays an important role in resisting ultraviolet radiation stress in C. elegans, probably in an insulin/IGF-1 signaling pathway-dependent way.

Knockdown of TRPM7 attenuates apoptosis and inflammation in neonatal necrotizing enterocolitis model cell IEC-6 via modulating TLR4/NF-κB and MEK/ERK pathways.

Objectives: Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal critical illness in neonatal infants. TRPM7 reportedly plays a role in human inflammatory bowel disease (IBD) and colorectal cancer, but the role of TRPM7 in the pathogenesis of NEC remains vague. Materials and Methods: The expression of TRPM7 was determined in intestinal tissues of NEC patients and lipopolysaccharide (LPS)-induced IEC-6 cells. Subsequently, a loss-of-function assay was performed to assess the effects of TRPM7 on cell apoptosis and inflammatory response in IEC-6 cells after LPS induction. Furthermore, the modulation of TRPM7 on TLR4/NF-κB and MEK/ERK signaling pathways was validated. Results: The expression of TRPM7 was higher in the intestinal tissues of NEC patients compared with the normal human intestinal tissues. Moreover, the expression level of TRPM7 was elevated in LPS stimulation IEC-6 cells. Knockdown of TRPM7 enhanced cell viability and suppressed apoptosis, accompanied by the decreased Bax/Bcl-1 ratio and cleaved-caspase3 expression in LPS-induced IEC-6 cells. Additionally, TRPM7 silencing attenuated LPS-induced expressions and secretions of proinflammatory cytokines. Mechanistically, TRPM7 knockdown inhibited the TLR4/NF-κB activation, while enhancing the MEK/ERK activation in LPS-treated IEC-6 cells. Overexpression of TLR4 or inhibition of MEK attenuated the inhibitory effects of TRPM7 knockdown on LPS-induced apoptosis and inflammation in IEC-6 cells. Conclusion: Knockdown of TRPM7 attenuated LPS-induced IEC-6 cell apoptosis and inflammation by modulating TLR4/NF-κB and MEK/ERK pathways.

2D Cu-Bipyridine MOF Nanosheet as an Agent for Colon Cancer Therapy: A Three-in-One Approach for Enhancing Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a highly tumor-specific and minimally invasive treatment that is widely used in cancer therapy. However, its therapeutic effect is limited by the poor efficiency of hydroxyl radical generation. In colon cancer in particular, the high expression of hydrogen sulfide (H2S), which has strong reducibility, results in the consumption of generated hydroxyl radicals, further weakening the efficacy of CDT. To overcome this problem, we developed a novel two-dimensional (2D) Cu-bipyridine metal-organic framework (MOF) nanosheet [Cu(bpy)2(OTf)2] for colon cancer CDT. The therapeutic effect of Cu(bpy)2(OTf)2 is enhanced based on three factors. First, the developed 2D Cu-MOF rapidly consumes H2S to inhibit the consumption of generated hydroxyl radicals. Second, the ultrasmall CuS generated after H2S depletion facilitates Fenton-like reactions. Third, the generated CuS exhibits good photothermal performance in the second near-infrared window, allowing for photothermal-enhanced CDT. The ability of Cu(bpy)2(OTf)2 to improve the CDT effect was demonstrated through both in vitro and in vivo experiments. This work demonstrates the applicability of 2D Cu-MOF in the CDT of colon cancer and provides a novel strategy for constructing CDT agents for colon cancer.

Macrophages Loaded with Fe Nanoparticles for Enhanced Photothermal Ablation of Tumors.

Magnetic iron nanoparticle-based theranostics agents have attracted much attention due to their good magnetism and biocompatibility. However, efficiently enriching tumors with iron nanoparticles to enhance the treatment effect remains a pressing challenge. Herein, based on the targeting and high phagocytosis of macrophages, an Fe nanoparticle-loaded macrophage delivery system was designed and constructed to efficiently deliver iron nanoparticles to tumors. Hydrophilic Fe@Fe3O4 nanoparticles with a core-shell structure were synthesized by pyrolysis and ligand exchange strategy. Subsequently, they were loaded into macrophages (RAW264.7 cells) using a co-incubation method. After loading into RAW264.7, the photothermal performance of Fe@Fe3O4 nanoparticles were significantly enhanced. In addition, Fe@Fe3O4 nanoparticles loaded into the macrophage RAW264.7 (Fe@Fe3O4@RAW) exhibited a good T2-weighted MRI contrast effect and clear tumor imaging in vivo due to the tumor targeting tendency of macrophages. More importantly, after being intravenously injected with Fe@Fe3O4@RAW and subjected to laser irradiation, the tumor growth was effectively inhibited, indicating that macrophage loading could enhance the tumor photothermal ablation ability of Fe@Fe3O4. The macrophage mediated delivery strategy for Fe@Fe3O4 nanoparticles was able to enhance the treatment effect, and has great potential in tumor theranostics.

Hyaluronic acid-coated Bi:Cu2O: an H2S-responsive agent for colon cancer with targeted delivery and enhanced photothermal performance.

BACKGROUND: Endogenous hydrogen sulfide (H2S)-responsive theranostic agents have attracted extensive attention due to their specificity for colon cancer. However, the development of such agents with high enrichment in tumors and excellent photothermal performance remains challenging. RESULTS: We prepared hyaluronic acid (HA)-coated Bi-doped cuprous oxide (Bi:Cu2O@HA) via a one-pot method. The HA specifically targets colon cancer tumor cells to improve the enrichment of Bi:Cu2O@HA at tumor sites, while the doped Bi both enhances the photothermal performance of the H2S-triggered Cu2O and serves as an agent for tumor imaging. The results in this work demonstrated that the Bi:Cu2O@HA nanoparticles exhibit good biocompatibility, target colon cancer tumor cells, facilitate computed tomography imaging, and enhanced H2S-responsive photothermal therapy performance, resulting in an excellent therapeutic effect in colon cancer. CONCLUSIONS: The novel Bi:Cu2O@HA nanoparticles exhibit excellent tumor targeting and photothermal therapeutic effects, which provide new strategies and insights for colon cancer therapy.

A multifunctional nanoplatform delivering carbon monoxide and a cysteine protease inhibitor to mitochondria under NIR light shows enhanced synergistic anticancer efficacy.

Photoactivated chemotherapy has attracted widespread attention due to its ability to circumvent the shortcomings of hypoxia in tumor tissues compared with traditional photodynamic therapy. In this work, novel multifunctional nanoplatform (1), Ru-inhibitor@TPPMnCO@N-GQDs, was designed and prepared, which was capable of mitochondria-targeted co-delivery of the cysteine protease inhibitor and carbon monoxide (CO) stimulated with an 808 nm near infrared (NIR) laser. Nanoplatform (1) was prepared by covalent attachment of a mitochondria-targeted CO donor (TPPMnCO) and a Ru(II)-caged cysteine protease inhibitor (Ru-inhibitor) on the surface of fluorescent N-doped graphene quantum dots (N-GQDs). Nanoplatform (1) preferentially accumulated in the mitochondria of cancer cells and instantly delivered CO and the cysteine protease inhibitor upon 808 nm NIR light irradiation, thus damaging mitochondria and leading to significant in vitro and in vivo anticancer efficacy. In addition, nanoplatform (1) has good biocompatibility and did not exert any toxic side effects on mice during the period of treatment. The targeted subcellular mitochondrial co-delivery of CO and the cysteine protease inhibitor may provide new insights into CO and enzyme inhibitor combined therapies for cancer treatment.